Taina Lajunen

Mannose-binding lectin concentrations, MBL2 polymorphisms, and susceptibility to respiratory tract infections in young men.

BACKGROUND Mannose-binding lectin (MBL) is an important component of innate immunity, and its deficiency is associated with susceptibility to recurrent infections. METHODS This exploratory study investigated the association of serum MBL concentrations and MBL2 gene polymorphisms with respiratory tract infections in young men. We genotyped 6 single-nucleotide polymorphisms (SNPs) in the promoter region (alleles H/L, X/Y, and P/Q) and exon 1 (variant alleles B, C, and D and wild-type allele A) of the MBL2 gene by real-time polymerase chain reaction and measured serum MBL concentrations in 111 Finnish military recruits with asthma and 362 without. RESULTS An MBL level below the median concentration was a significant risk factor for infections (asthma status-adjusted odds ratio [OR], 2.5 [95% confidence interval {CI}, 1.4-4.5]). Among the 6 SNPs, there was a significant association between the promoter Y/Y genotype and infections (OR, 2.3 [95% CI, 1.2-4.4]) and a borderline significant association between exon 1 variant alleles and infections (OR, 1.7 [95% CI, 0.9-3.1]), after adjustment for asthma status. CONCLUSION These preliminary results suggest, for the first time, an association between MBL level and respiratory tract infections in young men and a possible association between infections and MBL2 polymorphisms.

Elevated MMP‐8 and Decreased Myeloperoxidase Concentrations Associate Significantly with the Risk for Peripheral Atherosclerosis Disease and Abdominal Aortic Aneurysm

Matrix metalloproteinases are responsible for degradation and remodelling of extracellular matrix and exert important roles in initiation and progression of inflammatory diseases. We aimed to examine the role of Matrix metalloproteinases (MMPs) and their regulators in degenerative arterial diseases. Serum samples were collected from patients with arterial disease (n = 126), who underwent surgery because of symptomatic aorto‐occlusive disease (AOD, n = 18), carotid artery stenosis (n = 67) or abdominal arotic aneurysm (n = 41). Serum MMP‐1, MMP‐8, MMP‐13, TIMP‐1, myeloperoxidase (MPO) and neutrophil elastase (HNE) concentrations were determined by ELISA, and the molar ratio of MMP‐8 and TIMP‐1 was calculated. To get reference values, the determinations were done on samples of healthy blood donors (n = 100). In univariate analyses, the patients had higher MMP‐8 (P < 0.001), TIMP‐1 (P = 0.045), and MMP‐8/TIMP‐1 (P < 0.001), and lower MPO (P < 0.001) when compared with the blood donors. All three subgroups had higher MMP‐8 (P < 0.001) and MMP‐8/TIMP‐1 (P < 0.001), and lower MPO (P < 0.01, except AOD) levels when compared with the references. In multiple logistic regression analyses, the male gender (P < 0.01), age (P < 0.001), elevated MMP‐8 (P < 0.001) and decreased MPO (P < 0.001) concentrations associated significantly with the risk for arterial disease, and provided an area under curve (AUC) of 0.97 in the Receiver operating characteristics analyses. In multiple linear regression analyses, HNE correlated with both MMP‐8 (P < 0.001) and MPO (P = 0.008) concentrations. Combination of high MMP‐8 and low MPO level in serum eventually reflecting selectively modified neutrophil degranulation may indicate increased risk for arterial disease.

Chlamydial LPS and high-sensitivity CRP levels in serum are associated with an elevated body mass index in patients with cardiovascular disease

Objective: Seropositivity for Chlamydia pneumoniae has been associated with an elevated body mass index (BMI). Our aim was to study if serum chlamydial lipopolysaccharide (cLPS), C. pneumoniae antibodies and high-sensitivity C-reactive protein (hsCRP) levels are associated with BMI Patients and Methods : The study population consisted of 174 patients with symptomatic carotid stenosis, abdominal aortic aneurysm or occlusive aortic disease. Information on BMI, diabetes, smoking, hypercholesterolemia, and statin medication was available. Serum C. pneumoniae IgG and IgA antibodies, cLPS, hsCRP and total endotoxin activity (totLPS) were measured. Results: BMI correlated with cLPS (r = 0.197; P < 0.01) and with hsCRP (ρ = 0.195; P < 0.01); in addition, there was a positive correlation between cLPS and hsCRP (ρ = 0.499; P < 0.01). A trend of an increasing proportion of C. pneumoniae IgG positivity (titre ≥ 64; P = 0.018) and higher serum cLPS (P = 0.01) and hsCRP (P = 0.01) concentrations was observed across the BMI groups (BMI ≤ 24.9 kg/m2, BMI = 25.0—29.9 kg/m2, and BMI ≥ 30.0 kg/m2). Among the three BMI groups, 24.6%, 38.8%, and 48.3% were C. pneumoniae IgG-positive and the median (IQR) cLPS concentrations (ng/ml) of the groups were: 92.6 (50.8—167.0), 128.9 (76.4—163.9), and 146.4 (105.8—175.8), respectively. The median (IQR) hsCRP (mg/l) concentrations of the groups were: 1.70 (0.70—3.05) 1.70 (0.80—5.20), and 3.40 (1.45—8.55), respectively. These associations remained statistically significant in a multivariate analysis. Conclusions: Elevated serum cLPS levels were associated with an elevated BMI. This is a novel finding and it strengthens the link between chlamydial infection and obesity. A lack of association between totLPS and BMI suggests that the association between infection and an elevated BMI may be specific to certain pathogens.

Elevated MMP-8 and Decreased Myeloperoxidase Concentrations Associate Significantly with the Risk for Peripheral Atherosclerosis Disease and Abdominal Aortic Aneurysm1

Matrix metalloproteinases are responsible for degradation and remodelling of extracellular matrix and exert important roles in initiation and progression of inflammatory diseases. We aimed to examine the role of Matrix metalloproteinases (MMPs) and their regulators in degenerative arterial diseases. Serum samples were collected from patients with arterial disease (n = 126), who underwent surgery because of symptomatic aorto‐occlusive disease (AOD, n = 18), carotid artery stenosis (n = 67) or abdominal arotic aneurysm (n = 41). Serum MMP‐1, MMP‐8, MMP‐13, TIMP‐1, myeloperoxidase (MPO) and neutrophil elastase (HNE) concentrations were determined by ELISA, and the molar ratio of MMP‐8 and TIMP‐1 was calculated. To get reference values, the determinations were done on samples of healthy blood donors (n = 100). In univariate analyses, the patients had higher MMP‐8 (P < 0.001), TIMP‐1 (P = 0.045), and MMP‐8/TIMP‐1 (P < 0.001), and lower MPO (P < 0.001) when compared with the blood donors. All three subgroups had higher MMP‐8 (P < 0.001) and MMP‐8/TIMP‐1 (P < 0.001), and lower MPO (P < 0.01, except AOD) levels when compared with the references. In multiple logistic regression analyses, the male gender (P < 0.01), age (P < 0.001), elevated MMP‐8 (P < 0.001) and decreased MPO (P < 0.001) concentrations associated significantly with the risk for arterial disease, and provided an area under curve (AUC) of 0.97 in the Receiver operating characteristics analyses. In multiple linear regression analyses, HNE correlated with both MMP‐8 (P < 0.001) and MPO (P = 0.008) concentrations. Combination of high MMP‐8 and low MPO level in serum eventually reflecting selectively modified neutrophil degranulation may indicate increased risk for arterial disease.

Full-length visfatin levels are associated with inflammation in women with polycystic ovary syndrome

Eur J Clin Invest 2012; 42 (3): 321–328

Chlamydial lipopolysaccharide (cLPS) is present in atherosclerotic and aneurysmal arterial wall--cLPS levels depend on disease manifestation.

BACKGROUND The role of Chlamydia pneumoniae in peripheral atherosclerosis disease and abdominal aortic aneurysm (AAA) remains unclear. Chlamydial lipopolysaccharide (cLPS) detection is a method used conventionally in routine chlamydial diagnosis of gynecological or ophthalmic samples. METHODS We compared cLPS concentrations, as well as other markers of bacterial load, in plaques and sera of patients operated on for carotid artery stenosis (n=110), aorto-occlusive disease (n=22), or AAAs (n=50) at the Helsinki University Central Hospital. RESULTS The median levels of cLPS in plaques were 2.28, 0.80, and 0.29 ng/ml in AAA, aorto-occlusive disease, and carotid artery stenosis patients, respectively (P<.001, Kruskal-Wallis). cLPS in serum correlated with LPS binding protein levels (Spearmans rho=0.52, P<.001), suggesting that the presence of chlamydiae is sufficient to produce an innate immune response reaction in these patients. Serum inflammatory markers interleukin 6 and highly sensitive C-reactive protein also correlate with cLPS (Spearmans rho=0.42 and 0.51, respectively, P<.001). CONCLUSIONS cLPS is present in arterial disease, and the potential role of C. pneumoniae in the pathogenesis of both peripheral atherosclerosis disease and AAA should not be forgotten. cLPS has a positive correlation with serum inflammatory markers, but this is no proof of a causal association.

Effects of CD14, TLR2, TLR4, LPB, and IL-6 Gene Polymorphisms on Chlamydia pneumoniae Growth in Human Macrophages In Vitro

Chlamydia pneumoniae is an obligate intracellular gram‐negative bacterium, which causes respiratory infections in humans. It can infect various cell types, e.g. vascular endothelial cells, smooth muscle cells and monocyte‐derived macrophages in vitro. The susceptibility of macrophages from healthy individuals to C. pneumoniae infection is highly variable. In this study, we evaluated the effects of innate immunity genes CD14 −260 C>T, TLR2 Arg753Gln, TLR4 Asp299Gly, LBP Phe436Leu and IL6 −174 G>C polymorphisms on C. pneumoniae growth in human macrophages in vitro. The growth of C. pneumoniae was highest in CD14 −260 C>T TT genotype cells and the difference to CC and CT genotypes was statistically significant (P = 0.032 and 0.022 respectively). The G‐allele of the IL6 −174 G>C polymorphism had a positive influence on chlamydial growth; the difference was statistically significant only between CC and GC genotypes (P = 0.018). TLR2 Arg 753Gln, TLR4 Asp299Gly, LBP Phe436Leu polymorphisms showed no effect on chlamydial growth.

The Synergistic Effect of Heredity and Exposure to Second-Hand Smoke on Adult-Onset Asthma

RATIONALE Identification of the subpopulation especially susceptible to the adverse effects of second-hand smoke exposure (SHS) would be useful for preventive actions and interventions. OBJECTIVES To investigate whether asthmatic heredity indicates susceptibility to the effects of SHS on the risk of adult-onset asthma. METHODS A population-based incident case-control study of clinically defined adult-onset asthma and randomly drawn control subjects (adults 21-63 yr old) from a geographically defined area in South Finland. After excluding current and ex-smokers there were 226 cases and 450 disease-free control subjects. MEASUREMENTS AND MAIN RESULTS Our outcome measure was new adult-onset asthma. Parental asthma and recent SHS had a synergistic effect on the risk of asthma, the adjusted odds ratio being 1.97 (95% confidence interval, 1.12-3.45) for SHS; 2.64 (1.65-4.24) for parental asthma; and 12.69 (3.44-46.91) for their joint effect (relative excess risk due interaction, 9.08 [-0.22 to 43.18]). Synergistic effect followed a dose-dependent pattern with both recent and cumulative SHS exposures, with relative excess risk due interaction for parental asthma and over 100 SHS cigarette-years of 6.17 (0.57-19.16). CONCLUSIONS This is the first study showing that individuals with asthmatic heredity have a considerably increased risk of adult-onset asthma when exposed to SHS. SHS exposure has dose-dependent synergism with family history of asthma, the joint effect being stronger with higher exposure levels. Avoiding SHS could be an important preventive measure for reducing the risk of adult-onset asthma among those with asthmatic heredity. Asking about family history of asthma is a useful tool for identifying these susceptible individuals in clinical and preventive settings.

Comparison of polymerase chain reaction methods, in situ hybridization, and enzyme immunoassay for detection of Chlamydia pneumoniae in atherosclerotic carotid plaques

Chlamydia pneumoniae has been associated with cardiovascular diseases and has been shown by different methods to be present in atherosclerotic lesions. However, not all studies have found C. pneumoniae in atherosclerotic tissues. We compared polymerase chain reaction (PCR) methods, in situ hybridization (ISH), and measurement of chlamydial lipopolysaccharide (cLPS) by enzyme immunoassay (EIA) from homogenized atherosclerotic tissue in the detection of C. pneumoniae. In a study population of 110 patients with carotid artery disease, cLPS was found in 22.2%, and DNA by PCR was found in 34.3% and by ISH in 39.4% of the samples. Poor repeatability was shown to complicate PCR, and the technical problems inherent in ISH were not insignificant. In contrast, the cLPS EIA test was fast and easy to perform. If the sensitivity could be increased, for example, by testing multiple tissue pieces, cLPS EIA might provide a standardized commercial method for the detection of chlamydia in tissue samples, and it, thus, merits further characterization and validation in different patient populations.

Susceptibility of Human Monocyte‐macrophages to Chlamydia pneumoniae Infection In Vitro is Highly Variable and Associated with levels of Soluble CD14 and C. pneumoniae IgA and Human HSP‐IgG Antibodies in Serum

Chlamydia pneumoniae, an intracellular microbe, causes respiratory infections and may participate in the development of atherosclerosis. It is able to survive and multiply in macrophages. The susceptibility of monocyte‐macrophages from healthy individuals to C. pneumoniae infection in vitro was studied. Intracellular growth of C. pneumoniae, as an indicator of susceptibility to infection, was compared to serum levels of C‐reactive protein, soluble CD14 (sCD14), human heat shock protein (HSP)‐IgG, human HSP‐IgA, C. pneumoniae IgG and IgA antibodies. The production of C. pneumoniae in infected macrophages was highly variable, ranging from 0 to 638 chlamydial genomes per human genome. Chlamydia pneumoniae production associated positively with serum C. pneumoniae IgA (titre: ≥10) and hHSP‐IgG and negatively with sCD14 concentration. The association between sCD14 concentration, C. pneumoniae IgA and human HSP‐IgG antibodies and C. pneumoniae production was statistically significant only among males. Age and gender did not correlate with the production. We hypothesize that persons whose macrophages cannot restrict the growth of C. pneumoniae are more prone to chronic infection by this agent.